The role of bone marrow-derived cells in the origin of liver cancer revealed by single-cell sequencing
The role of bone marrow-derived cells in the origin of liver cancer revealed by single-cell sequencing
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单细胞测序揭示骨髓来源细胞在肝癌起源中的作用
DOI：
10.20892/j.issn.2095-3941.2019.0369
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发表时间：
2020-02-01
影响因子：
5.5
通讯作者：
Zhang, Ning
中科院分区：
文献类型：
--
作者：
Chen, Lu;Yi, Xianfu;Zhang, Ning
目的：上皮癌常起源于祖细胞，而肝细胞癌（HCC）的起源仍存在争议。 HCC 是最致命的癌症之一，与肝损伤和慢性炎症密切相关，从而在肝脏修复过程中引发骨髓源性细胞 (BMDC) 的大量浸润。方法：为了探讨 BMDC 在 HCC 起源中的可能作用，我们在骨髓移植中建立了二乙基亚硝胺 (DEN) 诱导的 HCC 模型 老鼠。使用免疫组织化学和冰冻组织免疫荧光来验证DEN诱导的HCC疾病的病理学。通过单细胞测序、单细胞巢式PCR和免疫荧光-荧光原位杂交进一步研究了DEN诱导的HCC的细胞起源。结果：通过单细胞测序和生化分析的研究表明，这些小鼠的HCC细胞来自供体小鼠的BMDC，而不是来自受体小鼠。此外，先前在人类 HCC 中报道的几种 HCC 相关基因的小鼠直系同源物的拷贝数在我们的小鼠模型中也发生了改变。 DEN诱导的HCC表现出与人类HCC相似的组织学表型和基因组特征。结论：这些结果表明BMDC是HCC的重要起源，为HCC的预防、检测和治疗提供了重要线索。
Objective: Epithelial cancers often originate from progenitor cells, while the origin of hepatocellular carcinoma (HCC) is still controversial. HCC, one of the deadliest cancers, is closely linked with liver injuries and chronic inflammation, which trigger massive infiltration of bone marrow-derived cells (BMDCs) during liver repair.Methods: To address the possible roles of BMDCs in HCC origination, we established a diethylnitrosamine (DEN)-induced HCC model in bone marrow transplanted mice. Immunohistochemistry and frozen tissue immunofluorescence were used to verify DEN-induced HCC in the pathology of the disease. The cellular origin of DEN-induced HCC was further studied by single cell sequencing, single-cell nested PCR, and immunofluorescence-fluorescence in situ hybridization.Results: Studies by using single cell sequencing and biochemical analysis revealed that HCC cells in these mice were coming from donor mice BMDCs, and not from recipient mice. Furthermore, the copy numbers of mouse orthologs of several HCC-related genes previously reported in human HCC were also altered in our mouse model. DEN-induced HCCs exhibited a similar histological phenotype and genornic profile as human HCCs.Conclusions: These results suggested that BMDCs are an important origin of HCC, which provide important clues to HCC prevention, detection, and treatments.